The enclosed study, The Drug Industry's Performance In Finishing Postmarketing Research (Phase IV) Studies, based on data obtained from the Food and Drug Administration through the Freedom of Information Act, paints a grim, dangerous picture. Pharmaceutical companies are systematically failing to fulfill their commitments to the FDA to do post-marketing (Phase IV) clinical studies of newly approved drugs, often required by the agency as a condition of approval. The results of Phase IV studies can provide important safety information to augment the FDA's voluntary adverse drug reaction reporting system and could lead to more expeditious safety labeling changes or the withdrawal from the market of a new drug, if necessary.

From 1990 through 1994 a total of 88 new molecular entities (NMEs) were approved which had at least one Phase IV commitment. Only 13 percent (11 of the 88) were classified by the FDA as complete as of December 1999 (see table 1, page 5). This means that for at least five and as long as 10 years after drug approval, all of the studies for 87 percent of these drugs had not been completed. For the 107 NMEs with Phase IV commitments approved between January 1995 and the end of 1999, not one drug has been classified by the agency as having completed commitments as of December 23, 1999.

Previous research by the Health Research Group sheds further light on the Phase IV study issue. In late 1998, we surveyed FDA Medical Officers, who review New Drug Applications, regarding their attitudes towards the quality of the agency's drug approval process. The Medical Officers' comments on the issue of relying on postmarketing studies for approval of new drugs included the following:

"Good idea but no way to enforce Phase IV studies. If sponsors don't do them correctly what recourse does FDA have? It's tough to pull a drug."

"My office director told me that he was going to overrule me because the sponsor (Wyeth-Ayerst) would just go over our heads to Capitol Hill. He felt it was best to approve the drug for an indication not studied and have the sponsors do a Phase IV post-marketing trial in support of the indication. I reminded him that this sponsor had failed to honor other Phase IV studies. He went ahead and approved the drug."

The Medical Officers stated in our survey that 28 drugs had been approved in the previous three years only because Phase IV studies were required.

FDA advisory committee members may be more likely to recommend the approval of a new drug when there are questions of its safety and effectiveness if the manufacturer commits to Phase IV safety and efficacy studies. But, if advisory committee members were aware of the extraordinary failure of manufacturers to honor their Phase IV commitments, they might be less likely to recommend approval of a new drug based on the promise of a Phase IV commitment when lingering safety and effectiveness exist. We therefore ask that you send copies of the enclosed report to all FDA advisory committee members.

Under the current system, the FDA has the authority to revoke approval of some drugs for which Phase IV commitments have not been honored. This authority has never been invoked, nor is it clear that to do so would be in the best interests ofpatients. The FDA must ask for legislation to allow the agency to levy large civil monetary penalties against companies who fail to promptly finish phase IV study commitments.

Data obtained from the Food and Drug Administration (FDA) through a Freedom of Information Act (FOIA) request show that drug companies are failing to fulfill their postmarketing research (Phase IV) commitments. Phase IV studies are those that the FDA requires a company to perform after a drug has been approved and that are frequently a condition for a drug's approval. Although there are plausible additional explanations for this apparent poor performance, such as an inadequate system for tracking Phase IV studies at the FDA, neither explanation is acceptable from a public health perspective.

Phase IV studies constitute an important part of the postmarketing surveillance of new drugs. The results of Phase IV studies can provide important safety information to augment the FDA's voluntary adverse drug reaction reporting system and could lead to more expeditious safety labeling changes or the withdrawal from the market of a new drug, if necessary. In recent years, according to FDA officials, such studies have identified dangerous drug interactions between drugs not known at the time of marketing. In addition, drugs such as cholesterol-lowering drugs were approved with the knowledge that they were effective in lowering cholesterol but without clinical evidence that this translated into fewer heart attacks. FDA-required Phase IV studies were able to show that there was a clinical benefit as well and the labeling was modified accordingly.

The types of Phase IV studies committed to by pharmaceutical manufacturers are diverse. For example, studies may focus on a specific adverse drug effect or a specific drug toxicity in a defined patient population (different age or gender groups) or can study the possibly toxic interaction between the drug and other drugs or foods. Phase IV studies may also seek to determine a drug's long-term effectiveness in studies that can last two years. Other, much shorter, studies examine a drug's interactions with other drugs or the way in which a drug is metabolized. Some Phase IV studies ascertain whether a drug product's chemistry or manufacturing can be improved.

In 1993, new regulations codified FDA's authority to require Phase IV studies for certain new drugs.[1] Under these regulations, when the FDA approves an application on the basis of a surrogate endpoint or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity, the agency can require Phase IV studies as a condition of approval. If these subsequent studies do not demonstrate effectiveness, if they reveal safety problems, or if they are not completed with due diligence, the FDA can, in principle, withdraw approval of the drug. However, we are aware of no example of an approved drug being removed from the market for this reason.

The Food and Drug Administration Modernization Act (FDAMA) of 1997 provided the FDA with additional authority for monitoring the progress of Phase IV studies.[2] Once these provisions of FDAMA are implemented, manufacturers who have committed to a Phase IV study must submit an annual report until the commitment is completed or terminated. In this document they report the progress of the commitment or the reasons for the failure of the company to undertake or complete the commitment. FDAMA also requires that information pertaining to the status of these commitments be made publicly available.[3]

METHODS

Through the FOIA we obtained from the FDA all Phase IV study commitments made by the drug industry for all drugs approved from January 1, 1990 through December 23, 1999. The information we obtained included the status of Phase IV commitments indicated as either "P" for drugs for which there were still studies pending or "C" for complete as determined by the FDA. As indicated by the FDA, "C" means that all Phase IV studies for a specific drug have been completed. We restricted our analysis to Phase IV commitments made for drugs approved for the first time in the U.S. (New Molecular Entities or NMEs) and did not include those drugs previously approved for a new use or drugs which are combinations of two older drugs.

The FDA data do not allow a precise determination of how many discreet Phase IV studies were committed to for each NME drug approved. Some NMEs were approved with only one Phase IV study indicated as the commitment, while others were approved with commitments to study a number of different questions. It may be possible to answer several questions with a single study.

Because of this difficulty in determining the actual number of studies committed to by a drug manufacturer, we analyzed our results on the basis of the number of NMEs with at least one Phase IV study commitment and determined whether the commitment(s) for that drug had been recorded as completed or pending by the FDA. We limited the primary analysis to NMEs approved between January 1, 1990 and December 31, 1994. This gives companies at least five years and, for some, as long as ten years to have completed their commitments.

RESULTS

From January 1, 1990 through December 23, 1999 a total of 306 NME drugs were approved for marketing by the FDA. The number of NME approvals ranged from lows of 21 in 1990 and 1994 to a high of 52 in 1996. At least one Phase IV commitment was made for 195 NMEs (64%). The percentage of NMEs per year with at least one Phase IV commitment ranged from a high percent in 1993 to a low of 33% in 1998 (Figure 1).

The number of NMEs with at least one Phase IV commitment was relatively constant from 1990 through 1997. The apparent downward trend after this time in the percentage of NMEs with at least one Phase IV commitment is unexplained as is the sharp reduction in that percentage seen in 1998.

Figure 2 below depicts the number of NMEs with at least one Phase IV commitment and the number of commitments classified by the FDA as complete for the years 1990 through 1999.

From 1990 through 1994 a total of 122 NMEs were approved. Of these, 88 (72%) were approved with at least one Phase IV commitment. Only 13 percent (11 of the 88) were classified by the FDA as complete as of December, 1999. Completion rates per year of approval ranged between 5% (1993) and 26% (1991). For the 107 NMEs with Phase IV commitments approved after 1994, no drug has been classified by the agency as complete as of December 23, 1999. These results are shown in Table 1.

Table 1 - NMEs with at Least One Phase IV Commitment from 1990 through 1999

1990 - 1994

1995 - 1999

Number of NMEs Approved with at Least 1 Phase IV Commitment

88

107

Number of Phase IV Commitments Completed as of 12/23/99

11

0

Percentage Completed

13%

0%

DISCUSSION

These FDA data demonstrate that only 13 percent of the 88 NMEs approved between January 1, 1990 and December 31, 1994 for which Phase IV commitments were made are classified by the agency as being complete. This result suggests grossly inadequate compliance by drug companies in meeting their Phase IV study commitments.

However, an additional possible explanation is the FDA's inability to accurately track Phase IV study commitments, despite the additional authority provided in 1997 by FDAMA. In May 1996, the Office of Inspector General of the Department of Health and Human Services issued a report regarding the FDA's oversight of Phase IV study commitments.[4] This study found that the FDA did not have formal standards or procedures for monitoring Phase IV studies or for establishing whether a postmarketing study commitment had been met by a drug company. The FDA did develop policies and procedures for tracking Phase IV commitments that were implemented in October 1996.[5] It therefore seems unlikely that the FDA's failure to establish formal standards for tracking Phase IV commitments can explain the very large proportion of commitments that have not been met three years after the corrective measures were implemented. If this, in fact, is the case it either represents agency incompetence at the highest level or inadequate budgetary resources that must be addressed by Congress.

Previous research by the Health Research Group sheds further light on the Phase IV study issue. In late 1998, we surveyed FDA Medical Officers, who review New Drug Applications, regarding their attitudes towards the quality of the agency's drug approval process.[6] The Medical Officers' comments on the issue of relying on postmarketing studies for approval of new drugs included the following:

"We don't trust that the companies will carry out Phase IV studies with due diligence, either before or after PDUFA [Prescription Drug Users Fee Act]."

"Post-marketing studies are frequently not completed. FDA has no power to ensure such commitments"

"Good idea but no way to enforce Phase IV studies. If sponsors don't do them correctly what recourse does FDA have? It's tough to pull a drug."

"The agency forfeits its most powerful weapon -- withholding approval. Essentially all Phase IV studies which are required are for safety reasons. If a problem is identified, the agency negotiates with the company for labeling changes. Withdrawal is extremely unlikely even if its problem is very serious."

"My office director told me that he was going to overrule me because the sponsor (Wyeth-Ayerst) would just go over our heads to Capitol Hill. He felt it was best to approve the drug for an indication not studied and have the sponsors do a Phase IV post-marketing trial in support of the indication. I reminded him that this sponsor had failed to honor other Phase IV studies. He went ahead and approved the drug."

These comments by FDA Medical Officers support the explanation that the failure of manufacturers to finish their Phase IV commitments is the most likely reason for the results of our study. This explanation is extremely troubling when taken together with the fact that the Medical Officers stated in our survey that 28 drugs had been approved in the previous three years only because Phase IV studies were required.

FDA advisory committee members operating under the belief that manufacturers are diligent in finishing their Phase IV commitments may be more likely to recommend the approval of a new drug when there are questions of its safety and effectiveness if that manufacturer commits to Phase IV safety and efficacy studies. On the other hand, if advisory committee members were aware of the extraordinary failure of manufacturers to finish their Phase IV commitments, they may be less likely to vote to recommend approval of a new drug based on the promise of a Phase IV commitment when lingering safety and effectiveness exist.

If the FDA lacks the financial resources to implement FDAMA's Phase IV tracking provisions, Congress must provide the necessary resources as soon as possible. In addition, if Congress is truly interested in assuring that drug companies comply with their Phase IV commitments, it will give the FDA the authority to levy civil monetary penalties against those companies that do not complete their commitments in a timely manner.

Public Citizen, Inc. and Public Citizen Foundation

Together, two separate corporate entities called Public Citizen, Inc. and Public Citizen Foundation, Inc., form Public Citizen. Both entities are part of the same overall organization, and this Web site refers to the two organizations collectively as Public Citizen.

Although the work of the two components overlaps, some activities are done by one component and not the other. The primary distinction is with respect to lobbying activity. Public Citizen, Inc., an IRS § 501(c)(4) entity, lobbies Congress to advance Public Citizen’s mission of protecting public health and safety, advancing government transparency, and urging corporate accountability. Public Citizen Foundation, however, is an IRS § 501(c)(3) organization. Accordingly, its ability to engage in lobbying is limited by federal law, but it may receive donations that are tax-deductible by the contributor. Public Citizen Inc. does most of the lobbying activity discussed on the Public Citizen Web site. Public Citizen Foundation performs most of the litigation and education activities discussed on the Web site.

You may make a contribution to Public Citizen, Inc., Public Citizen Foundation, or both. Contributions to both organizations are used to support our public interest work. However, each Public Citizen component will use only the funds contributed directly to it to carry out the activities it conducts as part of Public Citizen’s mission. Only gifts to the Foundation are tax-deductible. Individuals who want to join Public Citizen should make a contribution to Public Citizen, Inc., which will not be tax deductible.

To become a member of Public Citizen, click here. To become a member and make an additional tax-deductible donation to Public Citizen Foundation, click here.